Cardium Therapeutics, an operating unit of Taxus Cardium Pharmaceuticals Group Inc. (Trading Symbol: CRXM) has announced the publication of a review article in the Journal of Cardiovascular Pharmacology that concludes a gene therapy product promoting the growth of blood vessels is “highly warranted” to treat about 1 million U.S. heart-disease patients and 6 million more worldwide who are either ineligible or poor candidates for traditional angioplasty, stent placement or bypass surgery.

The review described significant progress in gene therapy that resulted from optimized techniques to deliver an effective vessel-growth-promoting gene to heart tissue of patients most likely to respond to such treatment, and was authored by Dr. Gabor M. Rubanyi, M.D., Ph.D., Chief Scientific Officer of Cardium Therapeutics. Using Cardium’s cardiovascular gene therapy, researchers have quantified significant improvements in cardiac blood flow in treated patients with 3-D visualization scans.

Rubanyi said improvements have been incorporated into the delivery of Cardium’s Generx product candidate in the ASPIRE Phase 3 gene therapy clinical study, which is currently underway in the Russian Federation.

“While the basic science was never in doubt, more than two decades of refinements were needed to develop a safe, effective and optimized gene therapy for coronary artery disease patients who don’t have other good treatment options,” Rubanyi said.

Growth of collateral coronary vessels is a natural response to chronic myocardial ischemia, or restricted blood flow in the heart. However, Rubanyi said up to 70 percent of patients with advanced coronary artery disease fail to grow collateral vessels, or develop too few to significantly increase blood flow. Furthermore, no current treatment options stimulate the growth of collateral vessels in these patients.

Optimized Delivery to the Heart

The Generx® (Ad5FGF-4) clinical study product candidate is designed to be administered to this patient group by an interventional cardiologist during a brief, one-time angiogram-like procedure using a standard balloon catheter. In the past two years, researchers at Cardium Therapeutics have optimized the delivery of Generx using two balloon-occlusion cycles – with introduction of Generx and co-administration of a permeability agent during the second occlusion.

In a paper published in 2012 in Human Gene Therapy Methods, researchers at Emory University School of Medicine and Cardium Therapeutics reported that transgene expression in the hearts of pigs increased more than 100-fold compared with delivery without the occlusion cycles.

More Relevant Endpoint

In two earlier clinical trials of Cardium’s Generx product candidate, improved exercise tolerance test (ETT) performance on treadmills was used as the endpoint. In ETT tests, patients rely on their individually subjective discomfort levels to decide when to step off the treadmill. However, treadmill test results vary for a given patient from day to day. Placebo effects in control patients can be significant, and results also vary depending on participants’ fluctuating disease symptoms or complications of unrelated prescription medications.

A clinical trial of Generx conducted by Schering AG Germany and Berlex Laboratories in the United States, with whom Dr. Rubanyi was associated, employed a more sensitive and relevant endpoint: increased perfusion of blood in the heart eight weeks after treatment – as measured by the FDA-validated and widely used single photon emission computed tomography (SPECT) imaging system. Cardium has based its current international Phase 3 clinical trial on the SPECT endpoint, with results being evaluated by one of the world’s top cardiovascular imaging centers, the Nuclear Cardiology Core Laboratory at Cedars-Sinai Medical Center in Los Angeles. Following regulatory approval, it is not expected that SPECT would be required, and Generx would be administered to patients during a standard angiogram-like procedure. In the U.S., each year there are over 1.0 million angiograms performed.

Obstacles Overcome

“With significant improvements in gene therapy delivery, more relevant assessment of treatment and selection of patients who are likely responders, we’ve finally overcome the main obstacles to clinical success,” Rubanyi said.

Rubanyi’s review in Journal of Cardiovascular Pharmacology also summarizes all three current angiogenic gene therapy clinical trials in patients with coronary artery disease, each of which relies on a different growth-factor gene: vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), or ﬁbroblast growth factor (FGF).

Rubanyi said the FGF gene has proven to be one of the most suitable for therapeutic angiogenesis, since it exerts hierarchical control of vascular network formation.

“Although most of these growth factors were effective in preclinical models, scientiﬁc evidence suggests that FGFs may be the preferred choice for single growth factor therapy,” Rubanyi wrote. “Recent studies indicate that FGF can stimulate the release and action of other angiogenic factors necessary for the formation of new vascular networks.” The growth factors released by FGF include VEGF, HGF, platelet-derived growth factor (PDGF), and monocyte chemo-attractant protein-1 (MCP-1).

Interim Results of the Pivotal Phase 3 ASPIRE trial

In 2013, as part of the international clinical development program, the Russian Federation health regulators approved the Phase 3 ASPIRE study based on Cardium’s optimized delivery technique, more relevant endpoint, and inclusion of patients likely to respond to treatment.

Cardium announced the results of the prespecified interim analysis of the ASPIRE study at the Biotechnology Industry Organization (BIO) international convention on June 24, 2014: a statistically significant improvement at eight weeks of one-time Generx-treated patients versus controls in reversible perfusion defect size (RPDS) measured by SPECT. “The observed improvement in RPDS is similar in magnitude to that seen following heart-bypass surgery,” Rubanyi said.

Upon completion of the international Phase 3 trial, Christopher J. Reinhard, Chief Executive Officer of Cardium, said the results will be the basis for an application to the FDA for breakthrough-therapy designation.

Reinhard said about seven million people worldwide, including 1 million in the U.S., have been identified as potential beneficiaries of a one-time nonsurgical treatment with Generx. He said the therapy is a cost-effective way to treat such a large number of patients.

Generx (alferminogene tadenovec, Ad5FGF-4) is designed to be administered one-time, by an interventional cardiologist on an out-patient basis during a brief angiogram-like procedure using a standard balloon catheter. The Generx angiogenic gene therapy product candidate is designed to stimulate the body’s natural healing response to ischemic coronary artery disease by promoting the growth of microvascular circulation (collateral network) in the heart in order to enhance blood flow (cardiac perfusion). Generx is intended as a treatment for patients with myocardial ischemia and persistent angina pectoris (chest pain) due to coronary artery disease, despite optimal medical therapy and bypass surgery or percutaneous coronary intervention (PCI). In addition, this therapy could potentially benefit patients who are diagnosed with cardiac microvascular insufficiency, defined as myocardial ischemia without large vessel disease sufficient to cause ischemia. This group of patients, consisting of about 10-20 percent of patients with angina pectoris, is generally not helped by bypass surgery or PCI because these techniques are only applicable to identifiable and treatable lesions in large vessels, and not the growth of smaller vessels. The ASPIRE clinical study represents the fifth clinical study under the Generx gene therapy worldwide development program, which when completed will have evaluated over 780 patients at over 100 medical centers in the United States, Western Europe, South America, Canada and the Russian Federation, and is considered the largest cardiac gene therapy registration dossier in the world.

About Taxus Cardium Pharmaceuticals Group

Cardium Therapeutics, an operating unit of Taxus Cardium Pharmaceuticals Group Inc., is a development stage advanced regenerative therapeutics company that is focused on the late-stage clinical and commercial development of regenerative medicine therapeutics including (1) Generx®, an interventional cardiology, angiogenic gene therapy product candidate designed for the treatment of patients with cardiac microvascular insufficiency and myocardial ischemia due to advanced coronary artery disease; and (2) Excellagen®, an FDA-cleared flowable dermal collagen matrix designed as a professional-use advanced wound care product for the treatment of chronic non-healing diabetic, venous and pressure ulcers, which also has multiple additional potential tissue regeneration applications in combination with stem cells and other biologics (www.excellagen.com). For more information about Taxus Cardium's product development activities visit www.cardiumthx.com.

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